Toll-like receptors (TLRs) are a family of pattern recognition receptors (PRR) with a crucial function in innate immune responses. Activation of TLR4 signaling at the plasma membrane by lipopolysaccharide (LPS) stimulates proinflammatory signaling pathways dependent on the E3 ubiquitin ligase TRAF6. Here we show the LPS-induced long non-coding RNA (lncRNA) Mirt2 functions as a checkpoint to prevent aberrant activation of inflammation, and is a potential regulator of macrophage polarization. Mirt2 associates with, and attenuates Lys63 (K63)-linked ubiquitination of, TRAF6, thus inhibiting activation of NF-κB and MAPK pathways and limiting production of proinflammatory cytokines. Adenovirus mediated gene transfer of Mirt2 protects mice from endotoxemia induced fatality and multi-organ dysfunction. These findings identify lncRNA Mirt2 as a negative feedback regulator of excessive inflammation.

Primary Sjögren's syndrome is one of the most common autoimmune diseases. So far, genetic studies of Sjögren's syndrome have relied mostly on candidate gene approaches. To identify new genetic susceptibility loci for primary Sjögren's syndrome, we performed a three-stage genome-wide association study in Han Chinese. In the discovery stage, we analyzed 556,134 autosomal SNPs in 542 cases and 1,050 controls. We then validated promising associations in 2 replication stages comprising 1,303 cases and 2,727 controls. The combined analysis identified GTF2I at 7q11.23 (rs117026326: Pcombined = 1.31 × 10(-53), combined odds ratio (ORcombined) = 2.20) as a new susceptibility locus for primary Sjögren's syndrome. Our analysis also confirmed previously reported associations in Europeans in the regions of STAT4, TNFAIP3 and the major histocompatibility complex (MHC). Fine mapping of the region around GTF2I showed that rs117026326 in GTF2I had the most significant association, with associated SNPs extending from GTF2I to GTF2IRD1-GTF2I.

Vascular calcification is highly prevalent in end-stage renal diseases and is predictive of cardiovascular events and mortality. Poly(ADP-ribose) polymerase 1 (PARP1) inhibition or deletion is vasoprotective in several disease models. Here we show that PARP activity is increased in radial artery samples from patients with chronic renal failure, in arteries from uraemic rats, and in calcified vascular smooth muscle cells (VSMCs) in vitro. PARP1 deficiency blocks, whereas PARP1 overexpression exacerbates, the transdifferentiation of VSMCs from a contractile to an osteogenic phenotype, the expression of mineralization-regulating proteins, and calcium deposition. PARP1 promotes Runx2 expression, and Runx2 deficiency offsets the pro-calcifying effects of PARP1. Activated PARP1 suppresses miRNA-204 expression via the IL-6/STAT3 pathway and thus relieves the repression of its target, Runx2, resulting in increased Runx2 protein. Together, these results suggest that PARP1 counteracts vascular calcification and that therapeutic agents that influence PARP1 activity may be of benefit to treat vascular calcification.